Retinoids have shown promise for the prevention and treatment of cancer. Because of broad biological responses, natural and classical retinoids cause numerous side effects that have limited their use in clinic. The deciphering of retinoid signaling pathways, together with the discovery of selective compounds that can induce a restricted biological response, has revived interest in developing retinoids or retinoid related molecules (RRMs) for the treatment of various diseases. Certain RRMs can induce apoptosis in a number of cancer cell lines, including lung cancer cells, and have been shown to be effective against non-small cell lung cancer tumors in vivo. However, the mechanism of apoptosis induced by these compounds is not well understood. Interestingly, protein synthesis and/or mRNA transcription are not necessary for the RRM-mediated activation of caspases in Jurkat cells, suggesting a novel mechanism of action for this particular class of apoptotic retinoids. We have now observed that apoptotic retinoids cause a significant increase in Jun N-terminal kinase (JNK) and p38 kinase activities in lung cancer cells and they prevent TNF-mediated activation of NFkappaB. JNK and p38 have been shown to participate in the induction of apoptosis by certain stimuli in a cell type specific manner. In contrast, the activation of NFkappaB prevents apoptosis. We will investigate here the mechanism by which RRMs induce apoptosis in lung cancer cells. We will examine the role of JNK/p38 activation and NFkappaB inhibition in retinoid- induced apoptosis. The mechanisms of apoptosis induced by selective RRMS will be further examined in vivo. The potential outcome from the proposed research will provide valuable information on the mechanism of action of apoptosis inducing retinoids in lung cancer cells. Importantly, animal studies will confirm if retinoids can induce apoptosis in vivo through the activation of the same pathways as observed in vitro. Understanding the mechanism of action of these novel anti-cancer compounds should significantly enhance our abilities to develop optimal novel therapeutics for the treatment and prevention of lung cancer.